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PubMed2003

Structural basis of binding and inhibition of novel tarantula toxins in mammalian voltage-dependent potassium channels.

Voltage-dependent potassium channel Kv2.1 is widely expressed in mammalian neurons and was suggested responsible for mediating the delayed rectifier (I(K)) currents. Further investigation of the central role of this channel requires the development of specific pharmacology, for instance, the utilization of spider venom toxins. Most of these toxins belong to the same structural family with a short peptide reticulated by disulfide bridges and share a similar mode of action. Hanatoxin 1 (HaTx1) from a Chilean tarantula was one of the earliest discussed tools regarding this and has been intensively applied to characterize the channel blocking not through the pore domain. Recently, more related novel toxins from African tarantulas such as heteroscordratoxins (HmTx) and stromatoxin 1 (ScTx1) were isolated and shown to act as gating modifiers such as HaTx on Kv2.1 channels with electrophysiological recordings. However, further interaction details are unavailable due to the lack of high-resolution structures of voltage-sensing domains in such mammalian Kv channels. Therefore, in the present study, we explored structural observation via molecular docking simulation between toxins and Kv2.1 channels based upon the solution structures of HaTx1 and a theoretical basis of an individual S3(C) helical channel fragment in combination with homology modeling for other novel toxins. Our results provide precise chemical details for the interactions between these tarantula toxins and channel, reasonably correlating the previously reported pharmacological properties to the three-dimensional structural interpretation. In addition, it is suggested that certain subtle structural variations on the interaction surface of toxins may discriminate between the related toxins with different affinities for Kv channels. Evolutionary links between spider peptide toxins and a "voltage sensor paddles" mechanism most recently found in the crystal structure of an archaebacterial K(+) channel, KvAP, are also delineated in this paper.

Amino Acid Sequence↗
PubMedDate not supplied

Epithelium-dependent inhibition of cholinergic transmission in rat isolated trachea by potassium channel openers.

We have investigated the effects of the potassium channel openers, cromakalim and pinacidil, on cholinergic transmission in rat airways. Experiments were performed on epithelium-intact and epithelium-denuded preparations of rat isolated trachea which had been incubated with [3H]-choline to incorporate [3H]-acetylcholine into the cholinergic transmitter stores. In radiolabelled, epithelium-intact preparations, electrical field stimulation (60 s trains of 1 ms pulses, 5 Hz, 15 V) evoked an efflux of radioactivity that was unaffected by the removal of extracellular Ca2+ and, a large proportion of which was resistant to tetrodoxin (1 microM). In contrast, in epithelium-denuded preparations, both tetrodotoxin and Ca2+ withdrawal virtually abolished the stimulation-induced (S-I) efflux. Thus, with epithelium-denuded but not with epithelium-intact tracheal preparations, the S-1 efflux reflects the release of [3H]-acetylcholine from cholinergic nerves. Atropine (1 microM) markedly enhanced the S-I efflux in both epithelium-intact and epithelium-denuded preparations. In epithelium-intact preparations, the combination of atropine (1 microM) and tetrodotoxin (1 microM) reduced the S-I efflux to about the same level as did tetrodotoxin alone. Thus, in epithelium-intact tracheal preparations, when prejunctional muscarinic cholinoceptors subserving autoinhibition of transmitter release are blocked, S-I efflux may be taken as an index of transmitter acetylcholine release. Cromakalim (1 microM) had no effect on the S-I efflux from either epithelium-intact or epithelium-denuded tracheal preparations. However, in epithelium-intact preparations, when atropine (1 microM) was present, cromakalim (1 and 10 microM) and pinacidil (100 microM) significantly inhibited the S-I efflux. In epithelium-denuded preparations, in the presence of atropine (1 microM), cromakalim (1 microM) and pinacidil (100 microM) were without effect on S-I efflux. The inhibition of S-I efflux produced by cromakalim (1 microM) and pinacidil (100 microM) in epithelium-intact tracheal preparations (in the presence of atropine) was prevented by the ATP-sensitive potassium channel blocking drug glibenclamide (1 microM). Glibenclamide (1 microM) alone enhanced S-I efflux from epithelium-intact preparations in the absence but not in the presence of atropine (1 microM). Glibenclamide (1 microM) was without effect on S-I efflux in epithelium-denuded preparations both in the absence or presence of atropine (1 microM). In conclusion, the present study has provided additional evidence of an inhibitory action of the potassium channel openers, cromakalim and pinacidil, on the release of acetylcholine from parasympathetic nerves of the rat trachea which is dependent upon the functional integrity of the airway epithelium. The findings suggest that cromakalim and pinacidil may inhibit transmitter acetylcholine release by opening ATP-sensitive potassium channels, presumably on epithelial cells. In addition, the enhancement of S-I efflux from epithelium-intact tracheal preparations by glibenclamide may indicate that ATP-sensitive potassium channels on epithelial cells play a functional role in the modulation of transmitter acetylcholine release from parasympathetic cholinergic nerves of the airways.

Acetylcholine↗
PubMed1999

Roles of potassium channels and nitric oxide in modulation of uterine contractions in rat pregnancy.

OBJECTIVE: We sought to study the involvement of potassium channels in the inhibition by nitric oxide of spontaneous contractions in isolated uterine rings from midterm and term pregnant rats. STUDY DESIGN: Uterine rings from Sprague-Dawley rats at midterm and term gestation were used for isometric tension recording. The inhibition of spontaneous contractile activity by potassium channel openers and nitric oxide was studied in the absence and presence of potassium channel inhibitors. RESULTS: The adenosine triphosphate-dependent potassium channel opener levcromakalim inhibited spontaneous contractions in rings from both midterm and term pregnant rats in a concentration-dependent manner, and the effects were significantly attenuated by pretreatment with selective inhibitor of the adenosine triphosphate-dependent potassium channel inhibitor glibenclamide. The opener of calcium-dependent potassium channel NS 1619 inhibited spontaneous contractions in rings from midterm but significantly less so in rings from term pregnant rats in a concentration-dependent manner, and the effect was significantly attenuated by pretreatment with potassium channel inhibitors tetraethylammonium and tetrabutylammonium but not with glibenclamide. Rings from midterm and term pregnant rats were more sensitive to the inhibitory effect of levcromakalim compared with NS 1619. Nitric oxide donor diethylamine-nitric oxide inhibited spontaneous contractions in rings from midterm but significantly less in rings from term pregnant rats in a concentration-dependent manner, and the effect was attenuated by tetraethylammonium and tetrabutylammonium but not by glibenclamide. CONCLUSIONS: There is gestational age-dependent refractoriness to calcium-dependent potassium but not adenosine triphosphate-dependent potassium channel opener-induced inhibition of spontaneous contractile activity of isolated rat uterine rings. Nitric oxide inhibits uterine contractions by opening of calcium-dependent potassium channels in pregnant rat myometrium. Refractoriness to nitric oxide toward term may result from decreased probability to open or number of calcium-dependent potassium channels.

Adenosine Triphosphate↗
PubMed1998

Mechanosensitivity of the cardiac muscarinic potassium channel. A novel property conferred by Kir3.4 subunit.

Muscarinic potassium channels are heterotetramers of Kir3.1 and other Kir3 channel subunits and play major roles in regulating membrane excitability in cardiac atrial, neuronal, and neuroendocrine tissues. We report here that rabbit atrial muscarinic potassium channels are rapidly and reversibly inhibited by membrane stretch, possibly serving as a mechanoelectrical feedback pathway. To probe the molecular basis for this phenomenon, we heterologously expressed heteromeric Kir3.1/Kir3.4 channels in Xenopus oocytes and found that they possess similar mechanosensitivity in response to hypo-osmolar stress. This could be attributed in part, if not exclusively, to the Kir3.4 subunit, which reproduced the mechanosensitivity of the heteromeric channel when expressed as a homomeric channel in oocytes. Kir3.4 is the first stretch-inactivated potassium channel to be identified molecularly. Physiologically, this feature may be important in atrial volume-sensing and other responses to stretch.

Animals↗
PubMed1992

Recent progress in potassium channel opener pharmacology.

Potassium (K) channel openers comprise a diverse group of molecules capable of opening K channels in excitable cells. These agents exhibit their greatest potency in the smooth muscle system but K channels in cardiac muscle, neurones and in secretory cells are also affected. The development of tissue selectivity is currently one major focus of research and evidence is starting to emerge that this can be achieved. The profound effects of the K channel openers in vivo has led to the suggestion that an endogenous K channel opener might exist and exert an important role in blood pressure homeostasis. The discovery of such a substance--endothelium-derived hyperpolarizing factor--has many implications and its role in cardiovascular regulation is currently under investigation. In vivo, initial studies with the K channel openers emphasized their antihypertensive properties. However, later studies have concentrated on the improvement to coronary blood flow produced by these substances together with their protective effect on the ischaemic myocardium, the basis of which is not fully understood. In spite of great efforts, the K channel which forms the target of these agents in smooth muscle is a matter of controversy. The ability of glibenclamide to antagonize the actions of the K channel openers initially led to the suggestion that an ATP-dependent K channel was their site of action in smooth muscle although the most recent data have implicated a smaller conductance K channel.

Animals↗
PubMed1993

Inhibition of contractions of the isolated human myometrium by potassium channel openers.

OBJECTIVE: The aim was to investigate the properties of two potassium channel openers in human myometrium. STUDY DESIGN: The abilities of aprikalim and BRL 38227 to inhibit contractions produced by potassium chloride and oxytocin of myometrial strips from nonpregnant and pregnant women were studied. RESULTS: Aprikalim (1 and 10 mumol/L) and BRL 38227 (1 and 10 mumol/L) suppressed contractions induced by low (10 and 20 mmol/L) but not high (40 and 80 mmol/L) potassium chloride concentrations. Aprikalim and BRL 38227 were also potent relaxants of oxytocin (1 nmol/L)-induced contractions with rapid onset of action, of similar potency to each other, and reversible. Both compounds were significantly more potent against oxytocin (1 nmol/L)-induced contractions in myometrial strips from nonpregnant than from pregnant women. Aprikalim and BRL 38227, as relaxants of oxytocin-induced contractions, were antagonized by glibenclamide (1 mumol/L), a blocker of adenosine 5'-triphosphate-sensitive potassium channels. CONCLUSIONS: The results suggest that aprikalim and BRL 38227 relax the human myometrium by potassium channel opening, possibly at adenosine 5'-triphosphate-sensitive potassium channels. Compounds of this pharmacologic class are useful for investigating the physiologic functions of potassium channels in this tissue and could have a place in the treatment of dysmenorrhea and preterm labor.

Benzopyrans↗
PubMed1994

Cerebral vascular smooth muscle potassium channels and their possible role in the management of vasospasm.

One of the promising therapeutic uses of the potassium channel openers is in the management of cerebral vasospasm, a prolonged vasoconstriction of major cerebral arteries which follows aneurysmal subarachnoid haemorrhage. In this review, we first summarize the properties of potassium channels in cerebral vascular smooth muscle. Calcium-activated and ATP-dependent potassium channels are the major potassium channels identified in the cerebrovascular smooth muscle and both are believed to play a role in the regulation of cerebrovascular smooth muscle tone. The calcium-activated potassium channels can be activated by depolarization, by elevation of internal calcium and by some vasodilators. Some neuropeptides and potassium channel openers open the ATP-dependent potassium channels and produce vasodilation. We then review the effects of both synthetic and endogenous potassium channel openers in the cerebrovascular system, discuss their efficacy in the management of models of cerebrovascular spasm, and outline the clinical promise of these agents.

Adenosine Triphosphate↗
PubMed1996

Effects of potassium channel blockers on resting tone in isolated coronary arteries.

The effects of several potassium channel blockers on resting vasomotor tone were studied in porcine isolated coronary arteries. Coronary artery rings were suspended in organ baths for isometric tension recording. The nonselective potassium channel blockers tetraethylammonium (TEA 10(-5)-3 x 10(-2) M) and 4-aminopyridine (4-AP 10(-5)-10(-2) M) caused concentration-dependent contractions that were similar in rings with and without endothelium. The concentration-response curves to TEA and 4-AP were unaffected by treatment with phentolamine (3 x 10(-6) M),propranolol (10(-6) M), or atropine (10(-6) M). Diltiazem (10(-6) M) almost abolished the contractions evoked by TEA and 4-AP. Charybdotoxin (10(-9)-10(-7) M) and apamin (10(-8)-10(-6) M), selective blockers of large and small calcium-activated potassium channels, respectively, and glyburide (10(-8)-10(-6) M), a selective blocker of ATP-sensitive potassium channels, caused little or no contraction in rings with or without endothelium. Therefore, in isolated coronary arteries, TEA and 4-AP caused contractions that were independent of the release of vasoactive mediators from the endothelium or perivascular nerves. These effects are not mediated by ATP-sensitive potassium channels or by large and small conductance calcium-activated potassium channels. The data are consistent with an effect of TEA and 4-AP on resting membrane potassium conductance in coronary arteries, resulting in contractions that are sensitive to inhibition by diltiazem. This pattern of responsiveness of isolated coronary arteries to potassium channel blockers differs from that observed in vessels from other vascular beds.

4-Aminopyridine↗
PubMed2001

Kv beta subunit oxidoreductase activity and Kv1 potassium channel trafficking.

Voltage-gated Kv1 potassium channels consist of pore-forming alpha subunits and cytoplasmic Kv beta subunits. The latter play diverse roles in modulating the gating, stability, and trafficking of Kv1 channels. The crystallographic structure of the Kv beta2 subunit revealed surprising structural homology with aldo-keto reductases, including a triosephosphate isomerase barrel structure, conservation of key catalytic residues, and a bound NADP(+) cofactor (Gulbis, J. M., Mann, S., and MacKinnon, R. (1999) Cell 90, 943-952). Each Kv1-associated Kv beta subunit (Kv beta 1.1, Kv beta 1.2, Kv beta 2, and Kv beta 3) shares striking amino acid conservation in key catalytic and cofactor binding residues. Here, by a combination of structural modeling and biochemical and cell biological analyses of structure-based mutations, we investigate the potential role for putative Kv beta subunit enzymatic activity in the trafficking of Kv1 channels. We found that all Kv beta subunits promote cell surface expression of coexpressed Kv1.2 alpha subunits in transfected COS-1 cells. Kv beta1.1 and Kv beta 2 point mutants lacking a key catalytic tyrosine residue found in the active site of all aldo-keto reductases have wild-type trafficking characteristics. However, mutations in residues within the NADP(+) binding pocket eliminated effects on Kv1.2 trafficking. In cultured hippocampal neurons, Kv beta subunit coexpression led to axonal targeting of Kv1.2, recapitulating the Kv1.2 localization observed in many brain neurons. Similar to the trafficking results in COS-1 cells, mutations within the cofactor binding pocket reduced axonal targeting of Kv1.2, whereas those in the catalytic tyrosine did not. Together, these data suggest that NADP(+) binding and/or the integrity of the binding pocket structure, but not catalytic activity, of Kv beta subunits is required for intracellular trafficking of Kv1 channel complexes in mammalian cells and for axonal targeting in neurons.

Animals↗
PubMed2001

Potassium channel openers depolarize hippocampal mitochondria.

We investigated the effect of the potassium channel openers diazoxide and RP66471 on mitochondrial membrane potential and mitochondrial respiration in digitonin-treated rat hippocampal homogenates. Both diazoxide and RP66471 induced a dose-dependent decrease of mitochondrial membrane potential. Concomitant with the depolarization was an increase of mitochondrial respiration. Furthermore, the mitochondrial membrane depolarization induced by diazoxide and RP66471 was significantly larger in the presence of potassium ions than in the presence of sodium ions. The diazoxide-induced (but not RP66471-induced) mitochondrial membrane depolarization was partially inhibited by blockers of the ATP-regulated potassium channel, 5-hydroxydecanoic acid or the antidiabetic sulfonylurea glibenclamide. In addition, the potassium channel openers diazoxide and RP66471 increased mitochondrial matrix volume and induced a release of cytochrome c from hippocampal mitochondria. These results indicate the presence of a mitochondrial ATP-regulated potassium channel in rat hippocampus being a target for potassium channel openers.

Adenosine Triphosphate↗
PubMed2000

Single channel studies of inward rectifier potassium channel regulation by muscarinic acetylcholine receptors.

Negative regulation of the heartbeat rate involves the activation of an inwardly rectifying potassium current (I(KACh)) by G protein-coupled receptors such as the m2 muscarinic acetylcholine receptor. Recent studies have shown that this process involves the direct binding of G(betagamma) subunits to the NH(2)- and COOH-terminal cytoplasmic domains of the proteins termed GIRK1 and GIRK4 (Kir3.1 and Kir3.4/CIR), which mediate I(KACh). Because of the very low basal activity of native I(KACh), it has been difficult to determine the single channel effect of G(betagamma) subunit binding on I(KACh) activity. Through analysis of a novel G protein-activated chimeric inward rectifier channel that displays increased basal activity relative to I(KACh), we find that single channel activation can be explained by a G protein-dependent shift in the equilibrium of open channel transitions in favor of a bursting state of channel activity over a long-lived closed state.

Animals↗
PubMed2002

BMS-204352: a potassium channel opener developed for the treatment of stroke.

During ischemic stroke, a fatal biochemical cascade that results in neuronal hyperexcitability is initiated when neurons at risk are exposed to excessive excitatory amino acids and pathologically high levels of intracellular calcium (Ca(2+)). Therefore, neuroprotectants including NMDA-antagonists and blockers of voltage-gated Ca(2+) channels have been proposed as novel strategies for stroke treatment. Since potassium channels are key players in the control of neuronal excitability, and activation of neuronal potassium channels decrease excitability and neurotransmitter release, a novel approach for targeting acute ischemic stroke has been to develop openers of neuronal potassium channels. Bristol-Myers Squibb is developing BMS-204352, a fluoro-oxindole potassium channel opener, as a potential neuroprotectant for the treatment of acute ischemic stroke. BMS-203252 is a potent and effective opener of two important subtypes of neuronal potassium channels, the calcium-activated, big-conductance potassium channels (K(Ca) channels) and voltage-dependent, non-inactivating potassium channels known as KCNQ channels. BMS-204352 (0.3 mg/kg, i.v.) significantly reduced cortical infarct volume in a model of permanent occlusion of the middle cerebral artery (MCA) in spontaneous hypertensive rats (SHR), as compared to vehicle when administered 2 h post-occlusion. At doses from 1 microg/kg to 1 mg/kg i.v., BMS-204352 produced a significant reduction in cortical infarct volume in normotensive Wistar rats. In healthy humans, single and multiple i.v. doses of BMS-204352 (0.001 to 0.2 mg/kg) were safe, well-tolerated and without psychomotor function effects. Multiple doses of BMS-204352 (0.1-2 mg/kg i.v.) administered within 48 h after stroke onset were well tolerated in patients in Phase II studies, designed to evaluate safety, tolerability and pharmacokinetics. No clinically significant differences in organ toxicity or adverse effects were found, and total clearance and volume of distribution were independent of dose. BMS-204352 failed to show superior efficacy in acute stroke patients compared to placebo in a Phase III study that included 1978 patients at 200 centers worldwide.

Animals↗
PubMedDate not supplied

Potassium channel openers induce mitochondrial matrix volume changes via activation of ATP-sensitive K+ channel.

Recently, using patch-clamp method, an ATP-sensitive potassium channel in rat liver mitochondrial inner membrane was identified. In this report we investigated the effects of different potassium channel openers on potassium ion permeability of rat liver mitochondria. For that purpose we employed light scattering technique, reflecting mitochondrial volume changes linked to solute transport. Among various potassium channel openers RP 66471, pinacidil, minoxidil sulfate and KRN 2391 were found to stimulate mitochondrial swelling with high efficiency. P1060, aprykalim and diazoxide had only a slight effect, while Ro 31-6930 and nicorandil were found ineffective. Activation by the K+ openers was abolished by the antidiabetic sulfonylurea, glibenclamide (the well known blocker of ATP-sensitive potassium channels). These findings may suggest that mitochondrial ATP-dependent K+ channel is involved in regulation of mitochondrial matrix volume.

Adenosine Triphosphate↗
PubMed1990

Modification of potassium channel kinetics by histidine-specific reagents.

We have examined the actions of histidine-specific reagents on potassium channels in squid giant axons. External application of 20-500 microM diethylpyrocarbonate (DEP) slowed the opening of potassium channels with little or no effect on closing rates. Sodium channels were not affected by these low external concentrations of DEP. Internal application of up to 2 mM DEP had no effect on potassium channel kinetics. Steady-state potassium channel currents were reduced in an apparently voltage-dependent manner by external treatment with this reagent. The shape of the instantaneous current-voltage relation was not altered. The voltage-dependent probability of channel opening was shifted toward more positive membrane potentials, thus accounting for the apparent voltage-dependent reduction of steady-state current. Histidine-specific photo-oxidation catalyzed by rose bengal produced alterations in potassium channel properties similar to those observed with DEP. The rate of action of DEP was consistent with a single kinetic class of histidine residues. In contrast to the effects on ionic currents, potassium channel gating currents were not modified by treatment with DEP. These results suggest the existence of a histidyl group (or groups) on the external surface of potassium channels important for a weakly voltage-dependent conformational transition. These effects can be reproduced by a simple kinetic model of potassium channels.

Animals↗
PubMed2004

VKCDB: voltage-gated potassium channel database.

BACKGROUND: The family of voltage-gated potassium channels comprises a functionally diverse group of membrane proteins. They help maintain and regulate the potassium ion-based component of the membrane potential and are thus central to many critical physiological processes. VKCDB (Voltage-gated potassium [K] Channel DataBase) is a database of structural and functional data on these channels. It is designed as a resource for research on the molecular basis of voltage-gated potassium channel function. DESCRIPTION: Voltage-gated potassium channel sequences were identified by using BLASTP to search GENBANK and SWISSPROT. Annotations for all voltage-gated potassium channels were selectively parsed and integrated into VKCDB. Electrophysiological and pharmacological data for the channels were collected from published journal articles. Transmembrane domain predictions by TMHMM and PHD are included for each VKCDB entry. Multiple sequence alignments of conserved domains of channels of the four Kv families and the KCNQ family are also included. Currently VKCDB contains 346 channel entries. It can be browsed and searched using a set of functionally relevant categories. Protein sequences can also be searched using a local BLAST engine. CONCLUSIONS: VKCDB is a resource for comparative studies of voltage-gated potassium channels. The methods used to construct VKCDB are general; they can be used to create specialized databases for other protein families. VKCDB is accessible at http://vkcdb.biology.ualberta.ca.

Animals↗
PubMed2006

Control of single channel conductance in the outer vestibule of the Kv2.1 potassium channel.

Current magnitude in Kv2.1 potassium channels is modulated by external [K+]. In contrast to behavior expected from the change in electrochemical driving force, outward current through Kv2.1 channels becomes larger when extracellular [K+] is increased within the physiological range. The mechanism that underlies this unusual property involves the opening of Kv2.1 channels into one of two different outer vestibule conformations, which are defined by their sensitivity to TEA. Channels that open into a TEA-sensitive conformation generate larger macroscopic currents, whereas channels that open into a TEA-insensitive conformation generate smaller macroscopic currents. At higher [K+], more channels open into the TEA-sensitive conformation. In this manuscript, we examined the mechanism by which the conformational change produced a change in current magnitude. We started by testing the simplest hypothesis: that each pharmacologically defined channel conformation produces a different single channel conductance, one smaller and one larger, and that the [K+]-dependent change in current magnitude reflects the [K+]-dependent change in the percentage of channels that open into each of the two conformations. Using single channel and macroscopic recordings, as well as hidden Markov modeling, we were able to quantitatively account for [K+]-dependent regulation of macroscopic current with this model. Combined with previously published work, these results support a model whereby an outer vestibule lysine interferes with K+ flux through the channel, and that the [K+]-dependent change in orientation of this lysine alters single channel conductance by changing the level of this interference. Moreover, these results provide an experimental example of single channel conductance being modulated at the outer end of the conduction pathway by a mechanism that involves channel activation into open states with different outer vestibule conformations.

Algorithms↗
PubMed1998

Activation of large-conductance potassium channels in pregnant human myometrium by pinacidil.

OBJECTIVE: The aim was to investigate the effects of the potassium-channel opener pinacidil on single uterine potassium channels and the contribution of the latter to pinacidil-induced myometrial relaxation. STUDY DESIGN: Myometrial strips and freshly dispersed uterine myocytes were prepared from the myometrial biopsy samples of women undergoing elective, nonlabor caesarean section at term gestation. RESULTS: In isometric tension experiments pinacidil potently relaxed pregnant nonlabor human myometrial strips, with an agonist concentration yielding the half maximal response of 0.4 +/- 0.1 micromol/L. This effect was antagonized by 500 nmol/L charybdotoxin. Application of 10 micromol/L glibenclamide also inhibited the pinacidil-induced relaxation. Coapplication of charybdotoxin (500 nmol/L) and glibenclamide (10 micromol/L) produced a biphasic curve, which was fitted to a two-site model with values for agonist concentration yielding the half maximal response of 0.6 +/- 0.2 micromol/L and 189.7 +/- 0.8 micromol/L. Large-conductance calcium-dependent potassium channel activity was dramatically increased after application of pinacidil (between 10 and 100 micromol/L) to both inside-out and outside-out patches. The activation required the presence of calcium ions at the intracellular aspect of the membrane. Charybdotoxin but not glibenclamide blocked pinacidil-induced unitary large-conductance calcium-dependent potassium channel activity. CONCLUSION: Pinacidil-mediated relaxation of human pregnant myometrial strips may be partially attributable to the opening of uterine large-conductance calcium-dependent potassium channels in addition to adenosine triphosphate potassium channel activation. Drugs with specific potassium channel-activating properties may have important clinical application as novel tocolytics in the treatment of preterm labor.

Calcium↗
PubMed1986

Autoreceptor-mediated changes in dopaminergic terminal excitability: effects of potassium channel blockers.

The effects of the potassium channel blockers, 4-aminopyridine (4-AP) and tetraethylammonium (TEA), on autoreceptor-mediated changes in dopaminergic terminal excitability were examined in urethane-anesthetized rats. Local infusions of 4-AP or TEA into neostriatal terminal fields of nigral dopaminergic neurons led to marked decreases in terminal excitability, as measured by the increase in stimulating current required to activate the neurons antidromically from the site of the infusion. The decreased excitability resulting from 4-AP could be reversed by subsequent i.v. injection of haloperidol, and was blocked in rats that had been depleted of endogenous dopamine by prior treatment with alpha-methyl-p-tyrosine (AMpT). Thus, the decrease in excitability elicited by the potassium channel-blockers was indirect, and apparently due to increased autoreceptor stimulation resulting from enhanced transmitter release. In addition, co-infusion of 4-AP and apomorphine in AMpT-treated animals led to decreased terminal excitability that did not differ from the effects of apomorphine alone, indicating that 4-AP did not block the effects of exogenous autoreceptor agonist administration. These results provide in situ electrophysiological evidence that autoreceptor-mediated processes occurring at dopaminergic terminals are not mediated by 4-AP- or TEA-sensitive potassium channels. Furthermore, our findings suggest that, as in other types of presynaptic terminals, blockade of voltage-sensitive potassium channels in dopamine terminals leads to enhanced release of transmitter.

4-Aminopyridine↗